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The neuropeptide genes SST, TAC1, HCRT, NPY, and GAL are powerful epigenetic biomarkers in head and neck cancer: a site-specific analysis.

ABSTRACT: Background:Staging and pathological grading systems are convenient but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Identifying biomarkers for HNSCC that will progress and cause death is a critical research area, particularly if the biomarker can be linked to selection of patients. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of five neuropeptide gene promoters. The promoter methylation status was determined by quantitative methylation-specific PCR in 230 cases of HNSCC; 58 hypopharynx, 45 larynx, 56 oropharynx, and 71 oral cavity tumor samples were studied. Results:The somatostatin (SST), tachykinin precursor 1 (TAC1), hypocretin neuropeptide precursor (HCRT), neuropeptide Y (NPY), and galanin (GAL) promoters were methylated in 84.3, 63.5, 32.6, 28.3, and 20.0%, respectively, of the samples. The mean number of methylated genes per sample was 2.29 (range, 0-5). Disease-free survival was lower in patients with 3-5 methylated genes than in those with 0-2 methylated genes (log-rank test, P?=?0.007). In multivariate Cox proportional hazards analysis, TAC1 and GAL promoter methylation independently predicted recurrence (odds ratios 1.620, 95% confidence interval [CI] 1.018-2.578, P?=?0.042, and odds ratios 1.692, 95% CI 1.063-2.694, P?=?0.027, respectively). In patients with oral cancer, TAC1 methylation showed the best correlation with poor survival (odds ratio 4.427, 95% CI 1.634-12.00, P?=?0.003). Similar findings were observed for HCRT and GAL in patients with laryngeal cancer and oropharyngeal cancer, respectively. Conclusion:In this study, we demonstrated the methylation status of the neuropeptide-encoding genes SST, TAC1, HCRT, NPY, and GAL and its relationship with recurrence and survival in HNSCC. These methylation changes may serve as potential molecular markers for defining the risk and prognosis of HNSCC.

SUBMITTER: Misawa K

PROVIDER: S-EPMC5896056 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The neuropeptide genes SST, TAC1, HCRT, NPY, and GAL are powerful epigenetic biomarkers in head and neck cancer: a site-specific analysis.

Misawa Kiyoshi K Mima Masato M Imai Atsushi A Mochizuki Daiki D Misawa Yuki Y Endo Shiori S Ishikawa Ryuji R Kanazawa Takeharu T Mineta Hiroyuki H

Clinical epigenetics 20180411

<h4>Background</h4>Staging and pathological grading systems are convenient but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Identifying biomarkers for HNSCC that will progress and cause death is a critical research area, particularly if the biomarker can be linked to selection of patients. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of five neuropeptide gene promoters. The promoter methylation sta ...[more]

PMID: 29682090

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Project description:This study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells.The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15.Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population.Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ?-880? (2-bp TG/-, Ins/Del, rs3037354) minor/? allele was associated with several heritable (h(2)) stress traits: higher NPY secretion (h(2) = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ?-880? and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele -880? to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter -880? interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same -880? allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes.We conclude that common genetic variation at the NPY locus, especially in proximal promoter ?-880?, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states.

Dataset Information

The neuropeptide genes SST, TAC1, HCRT, NPY, and GAL are powerful epigenetic biomarkers in head and neck cancer: a site-specific analysis.

Publications

The neuropeptide genes <i>SST</i>, <i>TAC1</i>, <i>HCRT</i>, <i>NPY</i>, and <i>GAL</i> are powerful epigenetic biomarkers in head and neck cancer: a site-specific analysis.

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